The goal of this project is to assess and improve our understanding of the magnitude and clinical impact of (a) assumptions and approximations of current proton therapy regarding the physical interactions of protons with patient anatomy and treatment devices, (b) the markedly different dose distribution patterns of protons and photons, and (c) the assumption of the variability of the relative biological effectiveness (RBE) of protons compared to the current practice of using a constant RBE of 1.1. This goal will be accomplished partly through the analyses of clinical data (local control, toxicities and imaged response) from the P01 clinical trials and partly through computer simulations and through in-vivo experiments. Achieving this goal is of high significance in that the knowledge gained about the factors affecting treatment response (e.g., inter- and intra-fractional anatomic variations, approximations in predicting physical dose, RBE variability, etc.) would be critical for making reliable treatment decisions about the appropriateness of proton therapy, for correctly evaluating the clinical effectiveness of planned proton dose distributions, and for developing advanced methods to design optimum and robust IMPT to exploit the full potential of proton therapy. This project supports the mission of the NCI to improve the treatment and continuing care of cancer patients.